This research proposal outlines a 5-year career development plan for James C. Lo, M.D., Ph.D., cardiology fellow at Brigham and Women's Hospital and Harvard Medical School to achieve independence as a principal investigator under the mentorship of Bruce Spiegelman, Ph.D., Professor of Cell Biology and Medicine at the Dana-Farber Cancer and Harvard Medical School. Dr. Spiegelman is a member of the National Academy of Sciences and a world expert on adipose biology and metabolic diseases. Importantly, Dr. Spiegelman has a strong track record of mentoring scientists with over 20 trainees holding academic faculty positions. An advisory committee composed of Gkhan Hotamisligil, M.D, Ph.D. Professor at the Harvard School of Public Health, Diane Mathis, Ph.D. Professor at Harvard Medical School, and Evan Rosen, M.D., Ph.D. Associate Professor at Beth Israel Deaconess Medical Center will provide expertise on energy homeostasis, inflammation, stress, lipid metabolism, adipocyte lineage commitment/differentiation, and immune regulation. Dr. Lo will take advantage of the world class environment at the Spiegelman lab and surrounding Harvard Medical School campus, including the Dana-Farber Cancer Institute and Brigham and Women's Hospital to achieve the aims in the proposal. This plan allows Dr. Lo to develop expertise at the intersection of metabolic and inflammatory diseases and transition to an independent investigator. Obesity is an independent risk factor for cardiovascular disease. Recent studies have highlighted the intimate link between adipose tissue inflammation and metabolic diseases. Adipose inflammation drives the development of metabolic syndrome. Adipsin/complement factor D is an adipose-specific immune factor deficient in multiple models of obesity. Adipsin controls the rate-limiting step in the alternative complement pathway and generates the anaphylatoxin C3a, a potent immune activator. This places adipsin as a prime candidate to coordinate adipose tissue inflammation and the ensuing metabolic consequences of obesity and inflammation. The major objective of this project is to determine the function of adipsin in the pathogenesis of obesity and diabetes and to test whether adipsin-directed therapy can be an effective treatment for metabolic disease. The investigator will employ adipsin-deficient mice for in vivo metabolic studies, recombinant proteins within the adipsin pathway to dissect the mechanism, and test novel adipsin-directed therapies for treatment of obesity and diabetes. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading cause of mortality in the US and the recent trend of increasing prevalence of obesity and diabetes threaten to exacerbate this health problem. This career development award outlines a multi-step plan to understand the molecular link between metabolic and inflammatory diseases and to establish an independent investigator with expertise in this area. Understanding and being able to manipulate these pathways has the potential for development of novel therapies against obesity and diabetes.